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CTLA4 receptor and uses thereof
| Details |
Inventors: Linsley, Peter S.; Ledbetter, Jeffrey A.; Damle, Nitin K.; Brady, William; Kiener, Peter A.;
Assignee: Briston-Myers Squibb Company (Princeton, NJ)
Primary Examiner: Walsh; Stephen
Assistant Examiner: Lazar-Wesley; Eliane
Attorney, Agent or Firm: Mandel & Adriano
The invention identifies the CTLA4 receptor as a ligand for the B7 antigen. The complete amino acid sequence encoding human CTLA4 receptor gene is provided. Methods are provided for expressing CTLA4 as an immunoglobulin fusion protein, for preparing hybrid CTLA4 fusion proteins, and for using the soluble fusion proteins, fragments and derivatives thereof, including monoclonal antibodies reactive with B7 and CTLA4, to regulate T cell interactions and immune responses mediated by such interactions. |
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DETAILED DESCRIPTION OF THE INVENTION DEFINITION As used in this application, the following words or phrases have the meanings specified.
As used herein "blocking B7 interaction" means to interfere with the binding of the B7 antigen to its ligands such as CD28 and/or CTLA4 thereby obstructing T cell and B cell interaction.
As used herein a "B7-binding molecule" means any molecule which will bind the B7 antigen.
As used herein a "CTLA4 mutant" means a molecule having amino acids which are similar to the amino acid sequence of the extracellular domain of CTLA4 so that the molecule recognizes and binds a B7 antigen.
As used herein a "CD28 mutant" means a molecule having amino acids which are similar to the amino acid sequence of the extracellular domain of CD28 so that the molecule recognizes and binds a B7 antigen.
As used herein a "CTLA4/CD28 hybrid fusion protein" is a molecule having at least portions of the extracellular domains of both CTLA4 and CD28 so that the molecule recognizes and binds a B7 antigen.
As used herein a "non-CTLA4 protein sequence" means any molecule which does not bind B7 and does not interfere with the owning of CTLA4 to its B7 antigen target.
As used herein "the extracellular domain of CTLA4" is any portion of CTLA4 which recognizes and binds the B7 antigen.
For example, an extracellular domain of CTLA4 is that portion which is encoded by amino acid residues from about position 1 to about position 125 of the amino acid sequence corresponding to the extracellular domain of CTLA4 (FIG.
3).
As used herein "reactive with" means recognizes and binds its target.
As used herein a "fragment of CTLA4" is the extracellular domain of CTLA4 or portion thereof that recognizes and binds its target, e.
g.
, the B7 antigen.
As used herein a "derivative of CTLA4" is a molecule that shares at least 70% sequence homology with CTLA4 and functions like CTLA4, i.
e.
, it recognizes and binds the B7 antigen.
As used herein "blocks T cell proliferation" means to bind the B7 antigen on the B cell surface so that T cell proliferation is detectably inhibited by an art recognized test such as by nucleotide incorporation into DNA or clonogenic assay
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